Hepatitis is a general term meaning “inflammation of the liver” and has a number of causes mainly from viral origin. Hepatitis B is the most common serious liver infection in the world. It is caused by the hepatitis B virus (HBV) which is transmitted through blood and bodily fluids. The infection can occur through direct blood-to-blood contact, unprotected sex, use of contaminated needles, and from an infected woman to her newborn during the delivery process.
HBV is a hepatotrophic DNA virus belonging to the Hepadnaviridae family. The virus particle, virion, consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity similar to retroviruses (Locarnini S, 2004. Semin. Liver Dis. 24 (Suppl 1): 3-10). The outer envelope contains embedded proteins which are involved in viral binding and entry in susceptible cells. The full-length of the viral genome is about 3.2 kb, and it has four open reading frames (ORFs) including surface antigen (the “S gene”), core antigen (the “C gene”), DNA polymerase (the “P gene”) and a gene of undetermined function referred to as the “X gene” (Guo et al., 2009. Hbpd Int 8 (1): 59-64).
Infection with HBV may lead to acute or chronic hepatitis. In general, people who test positive for the hepatitis B virus for more than six months are diagnosed as having a chronic infection which might lead to liver failure, liver cancer or cirrhosis (Wolfram, Virol J. 2013; 10: 239 and Dienstag J L. Hepatitis B virus infection. N Engl J Med. 2008; 359:1486-1500).
The risk of developing a chronic hepatitis B infection is directly related to the age at which one becomes infected with the virus. Infants and young children are at the greatest risk for becoming chronically infected if exposed to the hepatitis B virus. For instance, 90% of exposed infants will develop chronic infections, 30-50% of exposed children will develop chronic infections and 10% of exposed adults will develop chronic infections. Persons with chronic HBV infection have up to a 300 times higher risk of developing hepatocellular carcinoma than persons without chronic HBV infection. Globally HBV causes 60-80% of the world's primary liver cancers. Every year about 1 million people worldwide die from chronic active hepatitis, cirrhosis or HBV-induced liver cancer. As a consequence, HBV ranks second only to tobacco as a known human carcinogen (www.cdc.gov/hepatitis/HBV, and www.mayoclinic.org/diseases-conditions/hepatitis-b/).
Although vaccines against HBV have been widely used for several decades, the HBV prevalence rate in the population still remains high. Current therapies for chronic HBV infection have only limited inhibitory effects on viral RNA and protein expression and typically suppress but do not eliminate the virus. For instance, the commonly used nucleoside reverse-transcriptase inhibitors Entecavir or Tenofovir suppress HBV replication in chronic HBV patients, but the effect is reversible if therapy is stopped. Moreover, despite the promise of therapeutic immunization for treating chronic HBV, the current HBV vaccine is not effective for therapeutic vaccination. Although it elicits a strong neutralizing antibody response that prevents infection, the current vaccine does not induce the CD8+ T cell response needed to eliminate the virus after infection. The current vaccine is also not optimal for widespread prophylactic vaccination in endemic developing regions of the world, as it does not protect all individuals, the antibody response wanes over time, and multiple doses are required for long-lasting immunity. An improved prophylactic vaccine that provides long-term immunity in a single dose, or an effective therapeutic vaccine that cures chronic HBV, would have a substantial impact on the prevention of HBV-associated chronic liver diseases.
For these reasons, there remains a need in the art for an effective HBV vaccine for both prophylactic and therapeutic use. The present invention addresses this need.